Liver failure and the associated brain malfunction is a major cause of morbidity and mortality in the United States, yet the etiology remains poorly understood. The encephalopathy associated with liver failure appears to be metabolic in origin and therefore potentially reversible. Therefore, knowledge of the mechanisms involved would enable the further development of sound therapeutic approaches: We recently found new evidence for the importance of ammonia in initiating a series of metabolic abnormalities characteristic of both chronic and acute hepatic encephalopathy, such as decreased brain glucose consumption, increased blood-brain barrier transport of neutral amino acids, and increased brain content of monoamine neurotransmitter precursor amino acids. Our experiments show that, contrary to previous opinion, ammonia itself is innocuous, and causes these abnormalities only on metabolism to glutamine. When glutamine synthetase is inhibited, the changes can largely be prevented or even reversed. We plan to investigate this in more detail, and to attempt to establish how glutamine synthesis leads to encephalopathy. We will study the effect of raised brain glutamine alone, inhibition of glutamine synthesis in established portalsystemic encephalopathy, the distribution of ammonia metabolism in brain, and the relationship with decreased glucose use and increased amino acid transport. Because GABA neurotransmission may be involved at a later stage in the chain of events leading to encephalopathy, we will study the effects of an antagonist of the benzodiazepine site on the GABA/A receptor, which has benefited some patients in hepatic coma. Acute or fulminant hepatic failure seems to share some characteristics of chronic liver disease with regard to its effects on cerebral function. To expand our knowledge from portalsystemic encephalopathy to fulminant hepatic encephalopathy, we will study models of acute liver failure. Our overall goal is to identify those common biochemical steps crucial to the development of encephalopathy in both acute and chronic liver failure.